Nitric oxide (NO) gas was considered to be a highly toxic pollutant as recently as the 1980s. It is now recognized to be an important messenger molecule in mammalian physiology. Inhaled NO is currently used to treat approximately 25,000 patients per year in this country with pulmonary hypertension. It is safe, effective, but costly. Published studies in which the per patient acquisition cost for bottled NO gas was over $5,000 suggest that even at that cost level, inhaled NO remains cost-effective compared with alternative, more invasive therapies such as extracorporeal membrane oxygenation. We are proposing to develop and test a compact point-of-care device that will generate unlimited quantities of NO gas at clinically useful concentrations from room air using a low-power electrical energy source. The device has the potential to eliminate cost as a factor in the utilization of NO inhalation therapy. In the proposed program, mass spectroscopy will be employed to characterize and optimize the output of the device. Its performance, mechanical endurance, and electrical safety also will be examined. We will then test its efficacy experimentally for a new and emerging application of NO for inhalation that we believe represents a rapid path to commercialization. As an adjunct in the treatment of malaria, NO inhalation appears to significantly prolong survival in experimental studies of severe malaria. While effective drug therapy for malaria exists, the disease is often in an advanced stage before therapy is begun, and many patients die before the drugs can take effect. Extending their survival with NO inhalation has the potential to be a means for salvaging a significant number of those patients. We will demonstrate that electrically-generated NO from the device is able to similarly prolong survival using a well-established murine model of severe malaria. Almost a million children under the age of 5 die each year from malaria in sub-Saharan Africa alone. In those regions where malaria is endemic, the limited available resources make it unlikely that NO inhalation using bottled gas is feasible. The proposed device may offer clinicians in under-developed countries a new tool for dealing with this major world health problem. Ultimately, we believe the device will also be employed for NO inhalation therapy for pulmonary hypertension in developed countries by virtue of the cost reduction it offers compared with using bottled gas. PUBLIC HEALTH RELEVANCE: The objective of this program is the development and evaluation of a point-of-care device to produce nitric oxide (NO) for inhalation from atmospheric nitrogen and oxygen. Presently used primarily as a life-saving therapy for treating newborns with hypoxia, NO inhalation also has the potential to be an important adjunct in the treatment of severe malaria, a disease that results in the death of an estimated 700,000 to 900,000 children under the age of five annually in sub-Saharan Africa alone.